The field of the invention is detection of genetic abnormalities in humans.
The hereditary retinal degenerative diseases ("HRD diseases") are a group of inherited conditions in which progressive, bilateral degeneration of retinal structures leads to loss of retinal function; these diseases include, for example, age-related macular degeneration, a leading cause of visual impairment in the elderly; Leber's congenital amaurosis, which causes its victims to be born blind; and retinitis pigmentosa ("RP"). RP is the name given to those inherited retinopathies which are characterized by loss of retinal photoreceptors (rods and cones), with retinal electrical responses to light flashes (i.e. electroretinograms, or "ERGs") that are reduced in amplitude. As the disease progresses, patients show attenuated retinal arterioles, and frequently show "bone spicule" pigmentation of the retina and waxy pallor of the optic discs.
The incidence of RP in the United States is estimated to be about 1:3500 births. Approximately 43% of cases in the state of Maine are from families with an autosomal dominant mode of transmission, 20% autosomal recessive, and 8% X-linked; 23% are isolated cases and 6% are undetermined (e.g., adopted) (Bunker et al., Am. J. Ophthalmol. 97:357-365, 1984). Genetic heterogeneity is thought to exist within each hereditary pattern. For example, linkage studies have revealed at least two distinct genetic loci for RP on the X-chromosome (Chen, Am. J. Hum. Genet. 45:401-411, 1989), another possibly near the rhesus locus on chromosome lp (Yijian et al., Cytogenet. Cell Genet. 46:614, 1987), and a fourth on the long arm of chromosome 3 (McWilliam et al., Genomics 5:619-622, 1989). Hence, RP is not one disease, but a group of diseases caused by mutations at various loci within the human genome.
Familial cases of RP usually present in childhood with night blindness and loss of midperipheral visual field due to the loss of rods in the peripheral retina. As the condition progresses, contraction of the visual fields eventually leads to blindness. Signs on fundus examination in advanced stages include retinal vessel attenuation, intraretinal pigment in the peripheral fundus, and waxy pallor of the optic disc. Patients have abnormal light-evoked electrical responses from the retina (i.e., electroretinograms or ERGs), even in the early stages in the absence of visible abnormalties on fundus examination. Histopathologic studies have revealed widespread loss of photoreceptors in advanced stages.